VOLUME 9 NUMBER 3 • SEPTEMBER 2012
129
SA JOURNAL OF DIABETES & VASCULAR DISEASE
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glucose lowering than many of the other
GLP-1 analogues.
Liraglutide, known in South Africa as Vic-
toza, has a half-life of between 11 and 13
hours, with a peak after nine to 12 hours.
It is broken down in the body and does not
get excreted via the kidney. It is marketed
as a once-daily dose and these two drugs
have been on the market for some time.
Comparative trials have been published.
Exenatide once a week, which is not
currently available in South Africa, is dosed
at 2 mg per week. The half-life is more than
24
hours. It is excreted by the kidneys. It
has a better effect on the fasting blood glu-
cose, compared to exenatide twice a day.
Gastrointestinal side effects appear to be
less than with the twice-daily dosing. Anti-
bodies develop against both formulations
of exenatide in about 50% of patients, but
this does not seem to impair the action to
a large extent.
Another molecule discussed was lix-
isenatide 20 µg per day, which has a half-
life of between 1.5 and three hours, with a
peak after two hours. Apparently the side
effects are less, but also the weight loss is
less impressive compared with exenatide.
This molecule needs further study.
In the pipeline is albiglutide, another
GLP-1 analogue, which has a half-life of
between six and eight days and a peak
after about five days. It achieves less weight
loss than the other analogues, and fewer
side effects, particularly nausea. It is a large
molecule, consisting of two copies of GLP-1
fixed to each other with an albumin tail.
The lack of weight loss may be because it
does not cross the blood-brain barrier.
Once-a-week exenatide versus liraglutide
was studied. Exenatide was shown to have
a slightly better HbA
1
c
lowering, as well as a
slight weight benefit but with more nausea
and vomiting, compared to liraglutide.
The conclusion was that there are many
GLP-1 analogues, which differ markedly
regarding the backbone, some of them
being exendin based and some GLP-mol-
ecule based, with slight changes or side
chains attached. They vary markedly in
size and pharmakokinetics and therefore
there is a difference in the clinical response
and side-effect profiles, as seen with other
classes of drugs. Further study is required.
Focus on basal insulin
In a session on insulin, Prof Jeremiah Boli
from Italy gave an excellent overview of
basal insulin. He commenced with NPH
insulin, which gives a peak of insulin after
four to six hours of subcutaneous injection,
often causing night-time hypoglycaemia,
especially in type 1 diabetes patients.
There is marked inter- as well as intra-
patient variability, which hampers titra-
tion of the dose. The duration of action is
too short and therefore twice-daily dosing
is needed. Prof Boli stated that this insu-
lin should definitely not be used for type
1
diabetes patients, and preferably not in
type 2 diabetes.
Glargine insulin is a peakless soluble
insulin with less variability than NPH and
gives 24-hour cover in most patients. It
is the best insulin for type 1 diabetes and
superior to NPH due to its lower risk for
hypoglycaemia.
Detemir is also a soluble insulin with
even less variability than glargine, but
shorter duration, less potency unit for
unit, and therefore often bigger doses are
needed for insulin-resistant patients. It is
used in a twice-daily dose in type 1 diabe-
tes patients. Its hypoglycaemic risk is low
and obese patients require more units per
kilogram body weight to achieve control.
Insulin degludec was offered as a poten-
tially favourable long-acting insulin. It is
injected as a di-heximer and forms multi-
heximers under the skin after injection. It
is then slowly released, giving very long
action, with a half-life of about 25 hours,
good 24-hour cover and no clear indication
of accumulation. There is a low hypogly-
caemic risk, low variability and the insulin
shows good pharmakokinetics.
Insulin degludec produced a similar HbA
1
c
level to that of glargine in comparative trials.
It had a low hypoglycaemic risk of 1.5 events
per patient years, versus glargine of 2.5
events per patient years. This was equivalent
to a relative risk reduction for hypoglycaemia
of 25% in one study, and 18% in another,
versus glargine. The absolute risk reduction
however was small. Insulin degludec gives
more flexibility for time of dosing because
of the long half-life.
Another interesting insulin that was dis-
cussed was the lispro polyethylene glycol
formulation, also known as pregilated
lispro. A study was presented on 137 type
1
diabetes patients, showing that this insu-
lin was superior to glargine. The patients
lost weight and there was an increase in
low-density lipoprotein (LDL) cholesterol
levels. HbA
1
c
lowering was superior in a
few cases. Hypoglycaemia was slightly
increased. There was an increase in liver
enzymes and this was a worrying potential
side effect that needs further clarification.
A second study of pregilated lispro on
fewer than 95 patients also showed weight
loss, with fewer hypoglycaemic incidents
than with glargine, and equivalent HbA
1
c
lowering. This insulin has potential but the
reasons for the weight loss as well as the
changes in liver enzyme levels should be
investigated.
In another talk in the same symposium,
Dr Luigi Menaghini presented new bolus
insulins and discussed normal human insu-
lin, which showed a 15 to 25% inter- and
intra-patient variability. It needs to be taken
between 30 and 45 minutes before meals
and has a delayed peak, often leading to
hypoglycaemia.
Analogues have been shown to cause
fewer incidents of hypoglycaemia than the
old insulins. They have a small benefit in
HbA
1
c
levels and are much safer. They work
more effectively if given 15 to 20 minutes
before meals.
An enzyme hyaluronidase has been
shown to enhance the action of insulin
analogues by as much as 200% and pro-
duces a much quicker action if given with a
short-acting analogue. This option is being
investigated currently.
Inhaled insulin was discussed and many
are still in phase 2 trials. Technosphere’s
insulin is apparently closest to coming on
the market. Inhaled insulin produces a
better fasting glucose level. It was com-
bined with gargine in a basal-bolus regi-
men. Incidents of hypoglycaemia were the
same compared to subcutaneous insulin.
It was mainly the ease of use and patient
satisfaction that was found to be supe-
rior.
Chronic cough was a notable side
effect, especially in the early weeks of
usage, but this tended to clear with con-
tinued use. However, lung-function tests
have shown decreased FEV1 and diffusion
capacity in the lungs and this needs fur-
ther clarification before inhaled insulin will
become a reality.
A trial was presented of glargine plus
inhaled insulin compared to NovoMix twice
a day. It showed equal HbA
1
c
lowering,
less weight gain, and better fasting glu-
cose levels. Hypoglycaemic incidents were
equivalent but coughing was a side effect.
In previous studies of inhaled insulin,
there was a trend towards more incidents
of lung cancer in patients who had smoked
previously. These drugs cannot be used in
current smokers and have the potential to
